CN104523598A - Glucan/adriamycin conjugate drug nano-particles and preparation method thereof - Google Patents
Glucan/adriamycin conjugate drug nano-particles and preparation method thereof Download PDFInfo
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Abstract
The invention provides glucan/adriamycin conjugate drug nano-particles. The nano-particles comprise a first repeat unit as shown in a formula I and a second repeat unit as shown in a formula II; in the formula II, R1 and R2 are from anyone independently selected from groups as shown in formulae 1-3. The invention further provides a method for preparing the glucan/adriamycin conjugate drug nano-particles. The method is simple and practical, and can be used for forming the glucan/adriamycin conjugate drug nano-particles with pH value sensitivity by using the anti-tumor drug adriamycin as a hydrophobic segment and an unconjugated glucan chain as a hydrophilic segment in a self-assembly mode. The conjugate drug nano-particles have excellent biocompatibility and EPR effect in the tumor position. Furthermore, when cRGDfk is introduced, the conjugate drug nano-particles have a function of active targeting, and can be used for efficiently transferring drugs.
Description
Technical field
The present invention relates to natural polymer/bonding medicine technical field, particularly relate to a kind of glucosan/adriamycin bonding medicine nano grain and preparation method thereof.
Background technology
Amycin (Doxorubicin), be otherwise known as many Suo Rou than star, adriamycin, the positive fourth mycin of 14-hydroxyl etc., be a kind of high efficiency anti-tumor medicine with broad-spectrum anti-tumor activity, its Main Function mechanism is the intercalation of DNA and suppresses the synthesis of nucleic acid.Amycin has strong cytotoxic effect, all has killing action to the tumor cell in various cycle, and therefore it is applicable to the chemotherapy of kinds of tumors.Clinically, amycin carries out chemotherapy mainly through the mode of intravenous administration, but, it is when being used alone, for body strong side effect as cause vomiting, alopecia, affect hemopoietic function of bone marrow and strong cardiac toxicity etc., not only bring huge misery to patient, and have impact on such medicine to a great extent and be applied even more extensively.
Relative to simple free drug, the existence that nano-carrier has benefited from " EPR effect " and have longer blood circulation time and the effect in focal area preferred accumulation, the treatment for tumor has potential huge advantage.And utilize the hydrophilic-hydrophobic structure that high molecule bonding medicine self is formed, nano-particle can be self-assembled into, this not only effectively can reduce medicine side effect brought over the course for the treatment of itself, and more can promote the Passive Accumulation of medicine at tumor locus, thus improve efficiency of transmission and the bioavailability of medicine.
At present, conventional polymer bond drug adjuvant mostly is the material with good biocompatibility, as Polyethylene Glycol (PEG), polylactic acid (PLA) etc.Wherein, glucosan (having another name called dextran, erythropoietin (EPO) etc.) is the natural macromolecule amylose material that a class has good biocompatibility, the main component of plasma substitute clinically, also be a kind of important excipient substance, be widely used in pharmaceutical preparation.In adriamycin bonding drug carrier, application number is in the Chinese patent literature of 201210512758.4, first by the different anhydride with pH sensitivity is modified amycin, then by adriamycin bonding in dextran molecule, prepared the glucosan-anhydride-adriamycin bonding medicine with different pH sensitivity; And the folic acid with cancer target effect is incorporated in described bonding medicine simultaneously.The bonding medical instrument of described introducing folic acid has the ability of certain pH sensitivity release.
In order to improve biocompatibility etc., application number is in the Chinese patent literature of 201310728141.0, reacts, obtain the Glucan-adriamycin conjugate drug with oxime bond structure after the buffer solution being dissolved with doxorubicin hydrochloride can being mixed with glucosan; Or react after the buffer solution being dissolved with doxorubicin hydrochloride is mixed with glucosan and sodium cyanoborohydride, obtain the Glucan-adriamycin conjugate drug with amido link structure.And at present, and research that direct self assembly form bonding medicine nano grain adriamycin bonded by glucosan schiff bases key have not been reported.
Summary of the invention
In view of this, the object of the present invention is to provide a kind of glucosan/adriamycin bonding medicine nano grain and preparation method thereof, glucosan provided by the invention/adriamycin bonding medicine nano grain has good biocompatibility and pH sensitivity, and its preparation method is simple, is beneficial to application.
The invention provides a kind of glucosan/adriamycin bonding medicine nano grain, comprise the first repetitive shown in formula I and the second repetitive shown in formula II:
In formula II, R
1and R
2independently selected from any one in the group shown in formula 1 ~ 3;
The degree of polymerization of described first repetitive is x, and the degree of polymerization of described second repetitive is y, 0.1≤x/y≤100.
Preferably, 6≤x≤12346; 1≤y≤12346.
The application provides the preparation method of a kind of glucosan/adriamycin bonding medicine nano grain, comprises the following steps:
The oxidized dextran being 1% ~ 91% by amycin source and oxidizability reacts in a solvent, and the temperature of described reaction is 0 DEG C ~ 60 DEG C, obtains glucosan/adriamycin bonding medicine nano grain;
Described glucosan/adriamycin bonding medicine nano grain comprises the first repetitive shown in formula I and the second repetitive shown in formula II:
In formula II, R
1and R
2independently selected from any one in the group shown in formula 1 and 2;
The degree of polymerization of described first repetitive is x, and the degree of polymerization of described second repetitive is y, 0.1≤x/y≤100.
The application also provides the preparation method of a kind of glucosan/adriamycin bonding medicine nano grain, comprises the following steps:
The oxidized dextran being 1% ~ 91% by amycin source and cRGDfk and oxidizability reacts in a solvent, and the temperature of described reaction is 0 DEG C ~ 60 DEG C, obtains glucosan/adriamycin bonding medicine nano grain;
Described glucosan/adriamycin bonding medicine nano grain comprises the first repetitive shown in formula I and the second repetitive shown in formula II:
In formula II, R
1and R
2independently selected from any one in the group shown in formula 1 ~ 3;
The degree of polymerization of described first repetitive is x, and the degree of polymerization of described second repetitive is y, 0.1≤x/y≤100.
Preferably, described oxidized dextran is prepared in accordance with the following methods:
Glucosan and sodium metaperiodate are reacted in water, obtains the oxidized dextran that oxidizability is 1% ~ 91%.
Preferably, the molecular weight of described glucosan is 1000g/mol ~ 2000000g/mol.
Preferably, described solvent is distilled water; Described amycin source is doxorubicin hydrochloride; Described reaction is carried out under pH value is the condition of 6.5 ~ 8.5, preferably 7.0 ~ 8.0.
Preferably, the time of described reaction is 3 days ~ 13 days.
Preferably, described solvent is dimethyl sulfoxide; Described amycin source is amycin.
Preferably, the time of described reaction is 12h ~ 160h.
Compared with prior art, glucosan/adriamycin bonding medicine nano grain that the application provides comprises: the first repetitive shown in formula I and the second repetitive shown in formula II.In the present invention, described glucosan/adriamycin bonding medicine nano grain is the natural macromolecular material glucosan of simple modification, has good biocompatibility; As the antitumor drug amycin just at Clinical practice, there is formula 1 structure, by schiff bases key and glucosan bonding, after medicine is bonded and makes bonding medicine nano grain, there is the EPR effect at tumor locus, greatly can reduce its toxic and side effects in vivo in cyclic process, and effectively can extend circulation time.The present invention is using antitumor drug amycin as hydrophobic section, using the dextran chain of non-bonding as hydrophilic section, the Glucan-adriamycin conjugate drug nanoparticle with pH sensitive is formed by self assembly, after it is by tumor cell endocytosis, by the fracture of the responsive schiff bases key of pH, former medicine amycin is released in cell, reaches the object of efficient killing off tumor cells.This bonding medicine nano grain, for reducing the toxic and side effects of amycin and improving drug effect, has positive clinical meaning and application prospect.Further, the present invention is to provide the simple preparation method of one of bonding medicine nano grain, be beneficial to application.
In addition, in the present invention, cRGDfk has formula 3 structure; Because it is the peptide molecule with tumor-targeting effect, when the present invention's introducing has the cRGDfk of target function, described bonding medicine nano grain is just provided with the function of active targeting, can transmit medicine more efficiently.
Accompanying drawing explanation
In order to be illustrated more clearly in the embodiment of the present invention or technical scheme of the prior art, be briefly described to the accompanying drawing used required in embodiment or description of the prior art below, apparently, accompanying drawing in the following describes is only embodiments of the invention, for those of ordinary skill in the art, under the prerequisite not paying creative work, other accompanying drawing can also be obtained according to the accompanying drawing provided.
Fig. 1 is the laser co-focusing photo after the obtained bonding medicine nano grain of the embodiment of the present invention 4 and A549 cell culture 1h;
Fig. 2 is the nuclear-magnetism phenogram of bonding medicine nano grain prepared by the embodiment of the present invention 5;
Fig. 3 is the DLS characterization data of the bonding medicine nano grain that the embodiment of the present invention 5 obtains;
Fig. 4 is the laser co-focusing photo after the obtained bonding medicine nano grain of the embodiment of the present invention 5 and A549 cell culture 1h;
Fig. 5 is the nuclear-magnetism phenogram of bonding medicine nano grain prepared by the embodiment of the present invention 6;
Fig. 6 is the DLS characterization data of the bonding medicine nano grain that the embodiment of the present invention 6 obtains;
Fig. 7 is the drug accumulation releasing curve diagram of bonding medicine nano grain under different pH condition that the embodiment of the present invention 9 obtains.
Detailed description of the invention
Be clearly and completely described the technical scheme in the embodiment of the present invention below, obviously, described embodiment is only the present invention's part embodiment, instead of whole embodiments.Based on the embodiment in the present invention, those of ordinary skill in the art, not making the every other embodiment obtained under creative work prerequisite, belong to the scope of protection of the invention.
The invention provides a kind of glucosan/adriamycin bonding medicine nano grain, comprise the first repetitive shown in formula I and the second repetitive shown in formula II:
In formula II, R
1and R
2independently selected from any one in the group shown in formula 1 ~ 3;
The degree of polymerization of described first repetitive is x, and the degree of polymerization of described second repetitive is y, 0.1≤x/y≤100.
The invention provides a kind of glucosan by schiff bases key bonding/adriamycin bonding medicine nano grain, it has the feature such as good biocompatibility and pH sensitivity.
In the present invention, described glucosan/adriamycin bonding medicine nano grain comprises the first repetitive shown in formula I, and it is glucan unit, has good biocompatibility.The degree of polymerization of described first repetitive is x, as preferably, and 6≤x≤12346, more preferably 50≤x≤8000.
Described glucosan/adriamycin bonding medicine nano grain comprises the second repetitive shown in formula II, and it is the oxidized dextran unit containing aldehyde radical after oxidation open loop.In the present invention, the degree of polymerization of described second repetitive is y, preferably 1≤y≤12346, more preferably 10≤y≤6000.Inventive polymers nanoparticle is the glucose molecule that glucose unit and oxidizing glucose units alternately are formed, and the degree of polymerization y of the degree of polymerization x of described first repetitive and the second repetitive meets: 0.1≤x/y≤100.
In second repetitive with formula II structure, R
1and R
2independently selected from any one in the group shown in formula 1 ~ 3; Work as R
1and R
2in have one at least for the group shown in formula 1, amycin medicine on glucan unit bonding.In the present invention, amycin has formula 1 structure, and it is just at the antitumor drug of Clinical practice; And the group shown in formula 2 is aldehyde radical.Former medicine amycin is by schiff bases key bonding, and after bonding medicine nano grain is by tumor cell endocytosis, by the fracture of the responsive schiff bases key of pH, former medicine amycin is released in cell, reaches the object of efficient killing off tumor cells.This bonding medicine nano grain, for reducing the toxic and side effects of amycin and improving drug effect, has positive clinical meaning and application prospect.
In the present invention, cRGDfk has formula 3 structure, and it is the peptide molecule with tumor-targeting effect, when the present invention's introducing has the cRGDfk of target function, described bonding medicine nano grain is just provided with the function of active targeting, can transmit medicine more efficiently.In one embodiment of the invention, R
1for the group shown in formula 2, R
2for the group shown in formula 1.In another embodiment of the present invention, R
1for the group shown in formula 1, R
2for the group shown in formula 3.
The bonding medicine nano grain that the embodiment of the present invention provides is red solid powder; Particle diameter is below 100 nanometers.In one embodiment of the invention, described bonding medicine water-soluble after radius be 43 nanometers (by DLS diameter characterizations); In another embodiment of the present invention, R
1for the group shown in formula 1, R
2for the group shown in formula 3, the radius after the described bonding medicine with active targeting function is water-soluble is 34 nanometers (by DLS diameter characterizations).
In the present invention, described glucosan/adriamycin bonding medicine nano grain is the natural macromolecular material glucosan of simple modification, has good biocompatibility.Further, the bonding medicine nano grain that the embodiment of the present invention provides has in the EPR effect of tumor locus and active targeting function.After amycin medicine is bonded and makes bonding medicine nano grain, there is the EPR effect at tumor locus, greatly can reduce its toxic and side effects in vivo in cyclic process, and effectively can extend circulation time.When the present invention's introducing has the cRGDfk of target function, described bonding medicine nano grain is just provided with the function of active targeting, can transmit medicine more efficiently.
Accordingly, this application provides the preparation method of a kind of glucosan/adriamycin bonding medicine nano grain, comprise the following steps:
The oxidized dextran being 1% ~ 91% by amycin source and oxidizability reacts in a solvent, and the temperature of described reaction is 0 DEG C ~ 60 DEG C, obtains glucosan/adriamycin bonding medicine nano grain;
Described glucosan/adriamycin bonding medicine nano grain comprises the first repetitive shown in formula I and the second repetitive shown in formula II:
In formula II, R
1and R
2independently selected from any one in the group shown in formula 1 and 2;
The degree of polymerization of described first repetitive is x, and the degree of polymerization of described second repetitive is y, 0.1≤x/y≤100.
In order to introduce the targeted molecular cRGDfk with target function further, present invention also provides the preparation method of a kind of glucosan/adriamycin bonding medicine nano grain, comprising the following steps:
The oxidized dextran being 1% ~ 91% by amycin source and cRGDfk and oxidizability reacts in a solvent, and the temperature of described reaction is 0 DEG C ~ 60 DEG C, obtains glucosan/adriamycin bonding medicine nano grain;
Described glucosan/adriamycin bonding medicine nano grain comprises the first repetitive shown in formula I and the second repetitive shown in formula II:
In formula II, R
1and R
2independently selected from any one in the group shown in formula 1 ~ 3;
The degree of polymerization of described first repetitive is x, and the degree of polymerization of described second repetitive is y, 0.1≤x/y≤100.
The present invention adopts simple preparation method, and obtained the bonding medicine nano grain of a kind of glucan derivative and amycin, it has good biocompatibility, pH sensitivity, tumor locus EPR effect and less toxic and side effects etc.
The oxidized dextran of certain mass and amycin source react by the embodiment of the present invention in a solvent, can antitumor drug amycin as hydrophobic section, using the dextran chain of non-bonding medicine as hydrophilic section, formed the glucosan/adriamycin bonding medicine nano grain with pH sensitivity by self assembly.
The present invention take oxidized dextran as raw material, and its oxidizability is 1% ~ 91%, is preferably 5% ~ 50%; Herein, described oxidizability refers to the percentage composition of the number of contained aldehyde radical in 100 glucan unit.In the present invention, the molecular weight of described oxidized dextran is preferably 6000g/mol ~ 2000000g/mol.The source of the present invention to described oxidized dextran is not particularly limited, and preferably prepares in accordance with the following methods:
Glucosan and sodium metaperiodate are reacted in water, obtains the oxidized dextran that oxidizability is 1% ~ 91%.
Glucosan and sodium metaperiodate react by the embodiment of the present invention in water, and described reaction is preferably carried out under the condition of lucifuge and stirring, after a period of time, obtains the oxidized dextran with certain aldehyde group content.
In embodiments of the present invention, the molecular weight of described glucosan is preferably 1000g/mol ~ 2000000g/mol, is more preferably 6000g/mol ~ 2000000g/mol.In one embodiment of the invention, after the glucosan intermediate water of certain mass is fully dissolved, add a certain proportion of sodium metaperiodate and react, and lucifuge stirring reaction a period of time.The concentration of described glucan aqueous solution is preferably 0.1g/L ~ 200g/L; The mass ratio of described glucan aqueous solution and sodium metaperiodate is preferably (0.5 ~ 10): 1.
The temperature that the present invention prepares the reaction of oxidized dextran is preferably 4 DEG C ~ 50 DEG C; Time is preferably 0.5h ~ 5h.Afterwards, gained reaction solution is joined in bag filter certain hour of dialysing by the embodiment of the present invention, and water is changed in timing; Finally by the solution lyophilizing after dialysis, obtain the oxidized dextran product with certain aldehyde group content.
After obtaining oxidized dextran, the embodiment of the present invention, by oxidized dextran and amycin source and solvent mixing, is 0 DEG C ~ 60 DEG C in temperature, reacts under the condition that is preferably 20 DEG C ~ 40 DEG C, obtain glucosan/adriamycin bonding medicine nano grain.Wherein, described amycin source includes but not limited to amycin and doxorubicin hydrochloride, and doxorubicin hydrochloride is doxorubicin hydrochloride well known to those skilled in the art.In an embodiment of the present invention, the mass ratio of described amycin source and glucosan is (1:99) ~ (50:50).
In the present invention, described solvent is reaction dissolvent, can be that distilled water is as intermediate water; Also can be dimethyl sulfoxide, be preferably dry dimethyl sulfoxide.In one embodiment of the invention, the oxidized dextran of certain mass and doxorubicin hydrochloride are fully dissolved in intermediate water, preferred lucifuge is stirred to whole dissolving, by reacting obtained glucosan/adriamycin bonding medicine nano grain.Wherein, can first oxidized dextran be joined in intermediate water, after fully dissolving, then add doxorubicin hydrochloride solid and carry out dissolving, reacting.Described reaction is preferably carry out under the condition of 6.5 ~ 8.5, preferably 7.0 ~ 8.0 at pH value; The pH value of reactant liquor can be regulated in above-mentioned scope with a certain amount of sodium hydroxide solution.The time of described reaction is preferably 3 days ~ 15 days, is more preferably 5 days ~ 12 days.
In another embodiment of the present invention, the oxidized dextran of certain mass and amycin are all joined in dry dimethyl sulfoxide, preferably react under the condition of lucifuge and stirring, obtained glucosan/adriamycin bonding medicine nano grain.Wherein, can first be joined by oxidized dextran in dry dimethyl sulfoxide, after fully dissolving, then the amycin solid adding certain mass reacts.The time of described reaction is preferably 12h ~ 160h, is more preferably 48h ~ 96h.Afterwards, the present invention preferably adds when stirring the buffer solution that pH value is 6.0 ~ 8.5, continues to stir certain hour.The volume of the described buffer solution added is preferably 0.5 ~ 10 times of dimethyl sulfoxide volume, is more preferably 1 ~ 6 times; The described buffer solution added is preferably phosphate buffered solution.
In addition, after obtaining oxidized dextran, the embodiment of the present invention also can by oxidized dextran, amycin source and cRGDfk and solvent mixing, is 0 DEG C ~ 60 DEG C, reacts under the condition that is preferably 20 DEG C ~ 40 DEG C, obtain glucosan/adriamycin bonding medicine nano grain in temperature.Wherein, cRGDfk is peptide molecule well known to those skilled in the art.In an embodiment of the present invention, the mass ratio of described amycin source and polypeptide can be 25:5,25:10,20:5,10:1.
The cRGDfk that the present invention adds certain mass reacts, and introduces the targeted molecular with target function, adds the function of the active targeting of bonding medicine nano grain, can transmit medicine more efficiently.The addition sequence of the present invention to targeted molecular cRGDfk and amycin source does not have special restriction, and the conditions such as the time of reaction are identical with the condition do not introduced in the technical scheme of cRGDfk above, do not repeat them here.
In one embodiment of the invention, first described oxidized dextran and doxorubicin hydrochloride can be reacted in water, react 1 day ~ 5 days, then add cRGDfk, continue reaction 5 ~ 10 days.In another embodiment of the present invention, can first described oxidized dextran and cRGDfk be reacted in dimethyl sulfoxide, reaction 12h ~ 36h, then adds amycin solid, continues reaction 24h ~ 120h, then adds the buffer solution of respective volume.
Obtain reactant liquor after reaction certain hour, the embodiment of the present application is loaded in bag filter certain hour of dialysing, and water is changed in timing.Finally by the reactant liquor lyophilizing after dialysis, the glucosan/adriamycin bonding medicine nano grain product of the solid powdery that obtains taking on a red color.In the present invention, described dialysis is preferably carried out under the condition of lucifuge; The time of described dialysis is preferably 2 days ~ 3 days.The pH value of described dialysis is preferably 6.5 ~ 8.5, is more preferably 7.0 ~ 8.0.
The present invention carries out nuclear-magnetism sign to the structure of products therefrom, and result shows, described product is the Glucan-adriamycin conjugate drug by schiff bases key bonding; Bonding dose can up to 17.8%, and medicine bonding efficiency can be 71.2%.In addition, cRGDfk also can be bonded on dextran molecule.According to the method that this area is conventional, after the present invention is water-soluble by products therefrom, carry out DLS diameter characterization.Result shows, the present invention can obtain the Glucan-adriamycin conjugate drug nanoparticle of particle diameter below 100 nanometers.
Products therefrom is carried out the drug accumulation releasing research under different pH condition by the present invention, and result shows, described bonding medicine nano grain has good pH sensitivity.The concentration of amycin in products therefrom is fixed as 0.01g/L by the present invention, and by itself and human lung adenocarcinoma cell (A549) Dual culture 1h, and carry out laser co-focusing analysis, analytical tool is Carl Zeiss LSM 780.Result shows, described bonding medicine nano grain can enter in cell; In addition, the bonding medicine nano grain with polypeptide cRGDfk group can enter in tumor cell quickly, thus transmits medicine more efficiently.
In order to understand the application further, describe particularly below in conjunction with glucosan/adriamycin bonding medicine nano grain that embodiment provides the application and preparation method thereof.
Embodiment 1
Be, after the glucosan intermediate water of 6000g/mol fully dissolves, add 50mg sodium metaperiodate by 300mg molecular weight, and at room temperature lucifuge stirring reaction 1.5h; Afterwards the reaction solution obtained is joined in bag filter the 48h that dialyses, change 5 water; Finally by the solution lyophilizing after dialysis, obtain the oxidized dextran product that oxidizability is 21%.
See table 1, the ingredient proportion of the bonding medicine synthesis that table 1 provides for the embodiment of the present invention 1 ~ 15 and comparative example.Be 6000g/mol by 80mg molecular weight, oxidizability be 21% oxidized dextran join in the dimethyl sulfoxide of 10mL drying, after fully dissolving, add 20mg amycin solid, at room temperature lucifuge stirs and reacts, and reacts 24 hours; Slowly adding when stirring the phosphate buffered solution that 10mL concentration is 5mM afterwards, continuing stirring 2 hours.The reactant liquor lucifuge obtained dialysed 2 ~ 3 days, and water is changed in timing, the pH value keeping dialysis solution is 7.0 ~ 8.0.The kermesinus dialysis solution lyophilizing finally will obtained, obtains red solid powdered product, and it is the Glucan-adriamycin conjugate drug nanoparticle by schiff bases key bonding.
The ingredient proportion of the bonding medicine synthesis that table 1 embodiment of the present invention 1 ~ 15 and comparative example provide
Embodiment 2
Be, after the glucosan intermediate water of 6000g/mol fully dissolves, add 30mg sodium metaperiodate by 300mg molecular weight, and at room temperature lucifuge stirring reaction 2h; Afterwards the reaction solution obtained is joined in bag filter the 48h that dialyses, change 5 water; Finally by the solution lyophilizing after dialysis, obtain the oxidized dextran product that oxidizability is 19%.
See table 1, be 20000g/mol by 90mg molecular weight, oxidizability be 19% oxidized dextran join in the dimethyl sulfoxide of 10mL drying, after fully dissolving, add 10mg amycin solid, at room temperature lucifuge stirs and reacts, and reacts 36 hours; Slowly adding when stirring the phosphate buffered solution that 10mL concentration is 5mM afterwards, continuing stirring 2 hours.The reactant liquor lucifuge obtained dialysed 2 ~ 3 days, and water is changed in timing, the pH value keeping dialysis solution is 7.0 ~ 8.0.The kermesinus dialysis solution lyophilizing finally will obtained, obtains red solid powdered product, and it is the Glucan-adriamycin conjugate drug nanoparticle by schiff bases key bonding.
Embodiment 3
Be, after the glucosan intermediate water of 20000g/mol fully dissolves, add 30mg sodium metaperiodate by 300mg molecular weight, and at room temperature lucifuge stirring reaction 2h; Afterwards the reaction solution obtained is joined in bag filter the 48h that dialyses, change 5 water; Finally by the solution lyophilizing after dialysis, obtain the oxidized dextran product that oxidizability is 19%.
See table 1, be 20000g/mol by 89mg molecular weight, oxidizability be 19% oxidized dextran join in the dimethyl sulfoxide of 10mL drying, after fully dissolving, add 10mg amycin solid, at room temperature lucifuge stirs and reacts, and reacts 24 hours; Add 1mgcRGDfk solid again, under continuing room temperature, lucifuge stirs 48 hours; Slowly adding when stirring the phosphate buffered solution that 10mL concentration is 5mM afterwards, continuing stirring 2 hours.The reactant liquor lucifuge obtained dialysed 2 ~ 3 days, and water is changed in timing, the pH value keeping dialysis solution is 7.0 ~ 8.0.The kermesinus dialysis solution lyophilizing finally will obtained, obtains red solid powdered product, and it is the Glucan-adriamycin conjugate drug nanoparticle by schiff bases key bonding.
Embodiment 4
Be, after the glucosan intermediate water of 40000g/mol fully dissolves, add 40mg sodium metaperiodate by 300mg molecular weight, and at room temperature lucifuge stirring reaction 1.5h; Afterwards the reaction solution obtained is joined in bag filter the 48h that dialyses, change 5 water; Finally by the solution lyophilizing after dialysis, obtain the oxidized dextran product that oxidizability is 22%.
See table 1, be 40000g/mol by 65mg molecular weight, oxidizability be 22% oxidized dextran join in the dimethyl sulfoxide of 10mL drying, after fully dissolving, add 10mgcRGDfk solid, at room temperature lucifuge stirs and reacts, and reacts 24 hours; Add 25mg amycin solid again, under continuing room temperature, lucifuge stirs 72 hours; Slowly adding when stirring the phosphate buffered solution that 10mL concentration is 5mM afterwards, continuing stirring 2 hours.The reactant liquor lucifuge obtained dialysed 2 ~ 3 days, and water is changed in timing, the pH value keeping dialysis solution is 7.0 ~ 8.0.The kermesinus dialysis solution lyophilizing finally will obtained, obtains red solid powdered product.
Described product is the Glucan-adriamycin conjugate drug nanoparticle by schiff bases key bonding; Itself and A549 co-culture of cells are analyzed according to method mentioned above by the present invention, and result is the laser co-focusing photo after the obtained bonding medicine nano grain of the embodiment of the present invention 4 and A549 cell culture 1h see Fig. 1, Fig. 1.In Fig. 1, lower gray scale (blueness) place represents nucleus, and around nucleus, (redness) place represents amycin.Result shows, described bonding medicine nano grain can enter in cell, and discharges medicine.
Embodiment 5
Be, after the glucosan intermediate water of 40000g/mol fully dissolves, add 40mg sodium metaperiodate by 300mg molecular weight, and at room temperature lucifuge stirring reaction 1.5h; Afterwards the reaction solution obtained is joined in bag filter the 48h that dialyses, change 5 water; Finally by the solution lyophilizing after dialysis, obtain the oxidized dextran product that oxidizability is 22%.
See table 1, be 40000g/mol by 75mg molecular weight, oxidizability be 22% oxidized dextran join in the dimethyl sulfoxide of 10mL drying, after fully dissolving, add 25mg amycin solid, at room temperature lucifuge stirs and reacts, and reacts 72 hours; Slowly adding when stirring the phosphate buffered solution that 10mL concentration is 5mM afterwards, continuing stirring 2 hours.The reactant liquor lucifuge obtained dialysed 2 ~ 3 days, and water is changed in timing, the pH value keeping dialysis solution is 7.0 ~ 8.0.The kermesinus dialysis solution lyophilizing finally will obtained, obtains red solid powdered product.
The present invention carries out nuclear-magnetism sign to the structure of products therefrom, and result is the nuclear-magnetism phenogram of bonding medicine nano grain prepared by the embodiment of the present invention 5 see Fig. 2, Fig. 2.As shown in Figure 2, amycin has successfully been bonded on dextran molecule, and described product is the Glucan-adriamycin conjugate drug by schiff bases key bonding.Bonding dose is 17.8%, and medicine bonding efficiency is 71.2%.
According to the method that this area is conventional, after the present invention is water-soluble by products therefrom, carry out DLS diameter characterization.Result is the DLS characterization data of the bonding medicine nano grain that the embodiment of the present invention 5 obtains see Fig. 3, Fig. 3.As shown in Figure 3, gained bonding medicine water-soluble after radius be 43 nanometers.
Products therefrom and A549 co-culture of cells are analyzed according to method mentioned above by the present invention, and result is the laser co-focusing photo after the obtained bonding medicine nano grain of the embodiment of the present invention 5 and A549 cell culture 1h see Fig. 4, Fig. 4.In Fig. 4, lower gray scale (blueness) place represents nucleus, and around nucleus, (redness) place represents amycin.Result shows, described bonding medicine nano grain can enter in cell, and discharges medicine.
In addition compared with Fig. 4, in Fig. 1, in cell, redness is brighter.Show that the bonding medicine nano grain with polypeptide cRGDfk group can enter in cell quickly, thus transmit medicine more efficiently.
Embodiment 6
Be, after the glucosan intermediate water of 40000g/mol fully dissolves, add 40mg sodium metaperiodate by 300mg molecular weight, and at room temperature lucifuge stirring reaction 1.5h; Afterwards the reaction solution obtained is joined in bag filter the 48h that dialyses, change 5 water; Finally by the solution lyophilizing after dialysis, obtain the oxidized dextran product that oxidizability is 22%.
See table 1, be 40000g/mol by 70mg molecular weight, oxidizability be 22% oxidized dextran join in the dimethyl sulfoxide of 10mL drying, after fully dissolving, add 5mgcRGDfk solid, at room temperature lucifuge stirs and reacts, and reacts 24 hours; Add 25mg amycin solid again, under continuing room temperature, lucifuge stirs 48 hours; Slowly adding when stirring the phosphate buffered solution that 10mL concentration is 5mM afterwards, continuing stirring 2 hours.The reactant liquor lucifuge obtained dialysed 2 ~ 3 days, and water is changed in timing, the pH value keeping dialysis solution is 7.0 ~ 8.0.The kermesinus dialysis solution lyophilizing finally will obtained, obtains red solid powdered product.
The present invention carries out nuclear-magnetism sign to the structure of products therefrom, and result is the nuclear-magnetism phenogram of bonding medicine nano grain prepared by the embodiment of the present invention 6 see Fig. 5, Fig. 5.As shown in Figure 5, amycin and cRGDfk have all successfully been bonded on dextran molecule, and described product is the Glucan-adriamycin conjugate drug by schiff bases key bonding.Bonding dose is 16.9%, and medicine bonding efficiency is 67.6%.
According to the method that this area is conventional, after the present invention is water-soluble by products therefrom, carry out DLS diameter characterization.Result is the DLS characterization data of the bonding medicine nano grain that the embodiment of the present invention 6 obtains see Fig. 6, Fig. 6.As shown in Figure 6, gained water-soluble with the bonding medicine of active targeting function after radius be 34 nanometers.
Fig. 3 and Fig. 6 shows, can prepare the Glucan-adriamycin conjugate drug nanoparticle of particle diameter below 100 nanometers by the method for the invention.
Embodiment 7
Be, after the glucosan intermediate water of 100000g/mol fully dissolves, add 300mg sodium metaperiodate by 300mg molecular weight, and at room temperature lucifuge stirring reaction 1.5h; Afterwards the reaction solution obtained is joined in bag filter the 48h that dialyses, change 5 water; Finally by the solution lyophilizing after dialysis, obtain the oxidized dextran product that oxidizability is 66%.
See table 1, be 100000g/mol by 80mg molecular weight, oxidizability be 66% oxidized dextran join in the dimethyl sulfoxide of 10mL drying, after fully dissolving, add 20mg amycin solid, at the temperature of 60 DEG C, lucifuge stirs and reacts, and reacts 12 hours; Slowly adding when stirring the phosphate buffered solution that 10mL concentration is 5mM afterwards, continuing stirring 2 hours.The reactant liquor lucifuge obtained dialysed 2 ~ 3 days, and water is changed in timing, the pH value keeping dialysis solution is 7.0 ~ 8.0.The kermesinus dialysis solution lyophilizing finally will obtained, obtains red solid powdered product, and it is the Glucan-adriamycin conjugate drug nanoparticle by schiff bases key bonding.
Embodiment 8
Be, after the glucosan intermediate water of 100000g/mol fully dissolves, add 150mg sodium metaperiodate by 300mg molecular weight, and at room temperature lucifuge stirring reaction 1.5h; Afterwards the reaction solution obtained is joined in bag filter the 48h that dialyses, change 5 water; Finally by the solution lyophilizing after dialysis, obtain the oxidized dextran product that oxidizability is 49%.
See table 1, be 100000g/mol by 50mg molecular weight, oxidizability be 49% oxidized dextran join in the dimethyl sulfoxide of 10mL drying, after fully dissolving, add 50mg amycin solid, at the temperature of 4 DEG C, lucifuge stirs and reacts, and reacts 120 hours; Slowly adding when stirring the phosphate buffered solution that 10mL concentration is 5mM afterwards, continuing stirring 2 hours.The reactant liquor lucifuge obtained dialysed 2 ~ 3 days, and water is changed in timing, the pH value keeping dialysis solution is 7.0 ~ 8.0.The kermesinus dialysis solution lyophilizing finally will obtained, obtains red solid powdered product, and it is the Glucan-adriamycin conjugate drug nanoparticle by schiff bases key bonding.
Embodiment 9
Be, after the glucosan intermediate water of 100000g/mol fully dissolves, add 60mg sodium metaperiodate by 300mg molecular weight, and at room temperature lucifuge stirring reaction 1h; Afterwards the reaction solution obtained is joined in bag filter the 48h that dialyses, change 5 water; Finally by the solution lyophilizing after dialysis, obtain the oxidized dextran product that oxidizability is 23%.
See table 1, be 100000g/mol by 90mg molecular weight, oxidizability be 23% oxidized dextran join in 10mL intermediate water, after abundant dissolving, add 10mg doxorubicin hydrochloride solid, the pH value of gained solution is regulated to be 7.0 ~ 8.0 by the NaOH solution that concentration is 0.1M, at room temperature lucifuge stirs and reacts, and reacts 7 days.The reactant liquor lucifuge obtained dialysed 2 ~ 3 days, and water is changed in timing, the pH value keeping dialysis solution is 7.0 ~ 8.0.The kermesinus dialysis solution lyophilizing finally will obtained, obtains red solid powdered product.
Described product is the Glucan-adriamycin conjugate drug nanoparticle by schiff bases key bonding; Bonding dose is 4.0%, and medicine bonding efficiency is 40%.
Products therefrom is carried out the drug accumulation releasing research under different pH condition by the present invention, and result is the drug accumulation releasing curve diagram of bonding medicine nano grain under different pH condition that the embodiment of the present invention 9 obtains see Fig. 7, Fig. 7.As can be seen from Figure 7, when pH value declines, drug releasing rate is obviously accelerated.Show that this bonding medicine nano grain has good pH sensitivity, lower pH value condition can impel schiff bases bond fission, thus accelerates the release of amycin.
Embodiment 10
Be, after the glucosan intermediate water of 100000g/mol fully dissolves, add 20mg sodium metaperiodate by 300mg molecular weight, and at room temperature lucifuge stirring reaction 1.5h; Afterwards the reaction solution obtained is joined in bag filter the 48h that dialyses, change 5 water; Finally by the solution lyophilizing after dialysis, obtain the oxidized dextran product that oxidizability is 12%.
See table 1, be 100000g/mol by 80mg molecular weight, oxidizability be 12% oxidized dextran join in 10mL intermediate water, after abundant dissolving, add 20mg doxorubicin hydrochloride solid, the pH value of gained solution is regulated to be 7.0 ~ 8.0 by the NaOH solution that concentration is 0.1M, at room temperature lucifuge stirs and reacts, and reacts 7 days.The reactant liquor lucifuge obtained dialysed 2 ~ 3 days, and water is changed in timing, the pH value keeping dialysis solution is 7.0 ~ 8.0.The kermesinus dialysis solution lyophilizing finally will obtained, obtains red solid powdered product.
Described product is the Glucan-adriamycin conjugate drug nanoparticle by schiff bases key bonding; Bonding dose is 9.3%, and medicine bonding efficiency is 46.5%.
Embodiment 11
Be, after the glucosan intermediate water of 100000g/mol fully dissolves, add 20mg sodium metaperiodate by 300mg molecular weight, and at room temperature lucifuge stirring reaction 1.5h; Afterwards the reaction solution obtained is joined in bag filter the 48h that dialyses, change 5 water; Finally by the solution lyophilizing after dialysis, obtain the oxidized dextran product that oxidizability is 12%.
See table 1, be 100000g/mol by 80mg molecular weight, oxidizability be 12% oxidized dextran join in 10mL intermediate water, after abundant dissolving, add 20mg doxorubicin hydrochloride solid, the pH value of gained solution is regulated to be 7.0 ~ 8.0 by the NaOH solution that concentration is 0.1M, at the temperature of 20 DEG C, lucifuge stirs and reacts, and reacts 5 days; Then add 5mgcRGDfk solid, at the temperature of 20 DEG C, continue lucifuge stirring react, react 7 days.The reactant liquor lucifuge obtained dialysed 2 ~ 3 days, and water is changed in timing, the pH value keeping dialysis solution is 7.0 ~ 8.0.The kermesinus dialysis solution lyophilizing finally will obtained, obtains red solid powdered product.
Described product is the Glucan-adriamycin conjugate drug nanoparticle by schiff bases key bonding; Bonding dose is 8.1%, and medicine bonding efficiency is 40.5%.
Embodiment 12
Be, after the glucosan intermediate water of 100000g/mol fully dissolves, add 15mg sodium metaperiodate by 300mg molecular weight, and at room temperature lucifuge stirring reaction 1.5h; Afterwards the reaction solution obtained is joined in bag filter the 48h that dialyses, change 5 water; Finally by the solution lyophilizing after dialysis, obtain the oxidized dextran product that oxidizability is 7.8%.
See table 1, be 100000g/mol by 80mg molecular weight, oxidizability be 7.8% oxidized dextran join in 10mL intermediate water, after abundant dissolving, add 20mg doxorubicin hydrochloride solid, the pH value of gained solution is regulated to be 7.0 ~ 8.0 by the NaOH solution that concentration is 0.1M, at the temperature of 35 DEG C, lucifuge stirs and reacts, and reacts 7 days.The reactant liquor lucifuge obtained dialysed 2 ~ 3 days, and water is changed in timing, the pH value keeping dialysis solution is 7.0 ~ 8.0.The kermesinus dialysis solution lyophilizing finally will obtained, obtains red solid powdered product.
Described product is the Glucan-adriamycin conjugate drug nanoparticle by schiff bases key bonding; Bonding dose is 6.4%, and medicine bonding efficiency is 32%.See table 2, table 2 is bonding medicine medicine bonding efficiency prepared by the embodiment of the present invention 5,6 and 9 ~ 12.As can be seen from Table 2, take oil phase as the medicine bonding efficiency of bonding efficiency a little more than aqueous synthesis method of solvent gained bonding medicine.
Bonding medicine medicine bonding efficiency prepared by table 2 embodiment of the present invention 5,6 and 9 ~ 12
Embodiment 13
Be, after the glucosan intermediate water of 100000g/mol fully dissolves, add 10mg sodium metaperiodate by 300mg molecular weight, and at room temperature lucifuge stirring reaction 1.5h; Afterwards the reaction solution obtained is joined in bag filter the 48h that dialyses, change 5 water; Finally by the solution lyophilizing after dialysis, obtain the oxidized dextran product that oxidizability is 5.4%.
See table 1, be 100000g/mol by 99mg molecular weight, oxidizability be 5.4% oxidized dextran join in 10mL dimethyl sulfoxide, after fully dissolving, add 1mg amycin solid, at room temperature lucifuge stirs and reacts, and reacts 72 hours; Slowly adding when stirring the phosphate buffered solution that 10mL concentration is 5mM afterwards, continuing stirring 2 hours.The reactant liquor lucifuge obtained dialysed 2 ~ 3 days, and water is changed in timing, the pH value keeping dialysis solution is 7.0 ~ 8.0.The kermesinus dialysis solution lyophilizing finally will obtained, obtains red solid powdered product, and it is the Glucan-adriamycin conjugate drug nanoparticle by schiff bases key bonding.
Embodiment 14
Be, after the glucosan intermediate water of 200000g/mol fully dissolves, add 50mg sodium metaperiodate by 300mg molecular weight, and at room temperature lucifuge stirring reaction 1.5h; Afterwards the reaction solution obtained is joined in bag filter the 48h that dialyses, change 5 water; Finally by the solution lyophilizing after dialysis, obtain the oxidized dextran product that oxidizability is 21%.
See table 1, be 200000g/mol by 80mg molecular weight, oxidizability be 21% oxidized dextran join in 10mL dimethyl sulfoxide, after fully dissolving, add 20mg amycin solid, at room temperature lucifuge stirs and reacts, and reacts 72 hours; Slowly adding when stirring the phosphate buffered solution that 10mL concentration is 5mM afterwards, continuing stirring 2 hours.The reactant liquor lucifuge obtained dialysed 2 ~ 3 days, and water is changed in timing, the pH value keeping dialysis solution is 7.0 ~ 8.0.The kermesinus dialysis solution lyophilizing finally will obtained, obtains red solid powdered product, and it is the Glucan-adriamycin conjugate drug nanoparticle by schiff bases key bonding.
Embodiment 15
Be, after the glucosan intermediate water of 500000g/mol fully dissolves, add 45mg sodium metaperiodate by 300mg molecular weight, and at room temperature lucifuge stirring reaction 1.5h; Afterwards the reaction solution obtained is joined in bag filter the 48h that dialyses, change 5 water; Finally by the solution lyophilizing after dialysis, obtain the oxidized dextran product that oxidizability is 19%.
See table 1, be 500000g/mol by 80mg molecular weight, oxidizability be 19% oxidized dextran join in 10mL dimethyl sulfoxide, after fully dissolving, add 20mg amycin solid, at the temperature of 50 DEG C, lucifuge stirs and reacts, and reacts 72 hours; Slowly adding when stirring the phosphate buffered solution that 10mL concentration is 5mM afterwards, continuing stirring 2 hours.The reactant liquor lucifuge obtained dialysed 2 ~ 3 days, and water is changed in timing, the pH value keeping dialysis solution is 7.0 ~ 8.0.The kermesinus dialysis solution lyophilizing finally will obtained, obtains red solid powdered product, and it is the Glucan-adriamycin conjugate drug nanoparticle by schiff bases key bonding.
Comparative example
Be, after the glucosan intermediate water of 2000000g/mol fully dissolves, add 60mg sodium metaperiodate by 300mg molecular weight, and at room temperature lucifuge stirring reaction 1.5h; Afterwards the reaction solution obtained is joined in bag filter the 48h that dialyses, change 5 water; Finally by the solution lyophilizing after dialysis, obtain the oxidized dextran product that oxidizability is 27%.
See table 1, be 2000000g/mol by 70mg molecular weight, oxidizability be 27% oxidized dextran join in 10mL dimethyl sulfoxide, after fully dissolving, add 30mgcRGDfk solid, at room temperature lucifuge stirs and reacts, and reacts 60 hours; Slowly adding when stirring the phosphate buffered solution that 10mL concentration is 5mM afterwards, continuing stirring 2 hours.The reactant liquor lucifuge obtained dialysed 2 ~ 3 days, and water is changed in timing, the pH value keeping dialysis solution is 7.0 ~ 8.0.The kermesinus dialysis solution lyophilizing finally will obtained, obtains red solid powdered product, and it is glucosan-cRGDfk key compound.
As seen from the above embodiment, glucosan/adriamycin bonding medicine nano grain that the application provides comprises: the first repetitive shown in formula I and the second repetitive shown in formula II.In the present invention, described glucosan/adriamycin bonding medicine nano grain is the natural macromolecular material glucosan of simple modification, has good biocompatibility; As the antitumor drug amycin just at Clinical practice, there is formula 1 structure, by schiff bases key and glucosan bonding, after medicine is bonded and makes bonding medicine nano grain, there is the EPR effect at tumor locus, greatly can reduce its toxic and side effects in vivo in cyclic process, and effectively can extend circulation time.The present invention is using antitumor drug amycin as hydrophobic section, using the dextran chain of non-bonding as hydrophilic section, the Glucan-adriamycin conjugate drug nanoparticle with pH sensitive is formed by self assembly, after it is by tumor cell endocytosis, by the fracture of the responsive schiff bases key of pH, former medicine amycin is released in cell, reaches the object of efficient killing off tumor cells.This bonding medicine nano grain, for reducing the toxic and side effects of amycin and improving drug effect, has positive clinical meaning and application prospect.Further, the present invention is to provide the simple preparation method of one of bonding medicine nano grain, be beneficial to application.
In addition, in the present invention, cRGDfk has formula 3 structure; Because it is the peptide molecule with tumor-targeting effect, when the present invention's introducing has the cRGDfk of target function, described bonding medicine nano grain is just provided with the function of active targeting, can transmit medicine more efficiently.
Claims (10)
1. glucosan/adriamycin bonding medicine nano grain, comprises the first repetitive shown in formula I and the second repetitive shown in formula II:
In formula II, R
1and R
2independently selected from any one in the group shown in formula 1 ~ 3;
The degree of polymerization of described first repetitive is x, and the degree of polymerization of described second repetitive is y, 0.1≤x/y≤100.
2. glucosan according to claim 1/adriamycin bonding medicine nano grain, is characterized in that, 6≤x≤12346; 1≤y≤12346.
3. a preparation method for glucosan/adriamycin bonding medicine nano grain, comprises the following steps:
The oxidized dextran being 1% ~ 91% by amycin source and oxidizability reacts in a solvent, and the temperature of described reaction is 0 DEG C ~ 60 DEG C, obtains glucosan/adriamycin bonding medicine nano grain;
Described glucosan/adriamycin bonding medicine nano grain comprises the first repetitive shown in formula I and the second repetitive shown in formula II:
In formula II, R
1and R
2independently selected from any one in the group shown in formula 1 and 2;
The degree of polymerization of described first repetitive is x, and the degree of polymerization of described second repetitive is y, 0.1≤x/y≤100.
4. a preparation method for glucosan/adriamycin bonding medicine nano grain, comprises the following steps:
The oxidized dextran being 1% ~ 91% by amycin source and cRGDfk and oxidizability reacts in a solvent, and the temperature of described reaction is 0 DEG C ~ 60 DEG C, obtains glucosan/adriamycin bonding medicine nano grain;
Described glucosan/adriamycin bonding medicine nano grain comprises the first repetitive shown in formula I and the second repetitive shown in formula II:
In formula II, R
1and R
2independently selected from any one in the group shown in formula 1 ~ 3;
The degree of polymerization of described first repetitive is x, and the degree of polymerization of described second repetitive is y, 0.1≤x/y≤100.
5. the preparation method according to claim 3 or 4, is characterized in that, described oxidized dextran is prepared in accordance with the following methods:
Glucosan and sodium metaperiodate are reacted in water, obtains the oxidized dextran that oxidizability is 1% ~ 91%.
6. preparation method according to claim 5, is characterized in that, the molecular weight of described glucosan is 1000g/mol ~ 2000000g/mol.
7. the preparation method according to claim 3 or 4, is characterized in that, described solvent is distilled water; Described amycin source is doxorubicin hydrochloride; Described reaction is carried out under pH value is the condition of 6.5 ~ 8.5.
8. preparation method according to claim 7, is characterized in that, the time of described reaction is 3 days ~ 13 days.
9. the preparation method according to claim 3 or 4, is characterized in that, described solvent is dimethyl sulfoxide; Described amycin source is amycin.
10. preparation method according to claim 9, is characterized in that, the time of described reaction is 12h ~ 160h.
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